Evidence for two types of potassium channel in human motor axons in vivo
Abstract
We have obtained evidence that human axons in vivo possess potassium channels similar to two types found in rat nerve, giving rise to a slowly activating potassium conductance and inward rectification. This was achieved non-invasively by tracking the thresholds of single motor axons in the forearm while applying polarizing currents. On average, human ulnar motor axons appear to have fewer outwardly rectifying potassium channels than rat nerves.
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Axonal excitability as an early biomarker of nerve involvement in hereditary transthyretin amyloidosis
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Ulnar motor and sensory axonal excitability studies were prospectively undertaken on 22 patients with pathogenic hereditary transthyretin amyloid (ATTRv) gene variants, 12 with large fibre neuropathy (LF+) and 10 without (LF-), with results compared to age- and sex-matched healthy controls.
In motor axons we identified a continuum of change from healthy controls, to LF- and LF+ ATTRv with progressive reduction in hyperpolarising threshold electrotonus (TEh40(10–20 ms): p = 0.04, TEh40(20–40 ms): p = 0.01 and TEh40(90–10 ms): p = 0.01), suggestive of membrane depolarisation. In sensory axons lower levels of subexcitability were observed on single (SubEx) and double pulse (SubEx2) recovery cycle testing in LF+ (SubEx: p = 0.015, SubEx2: p = 0.015, RC(2–1): p = 0.04) suggesting reduced nodal slow potassium conductance, which promotes sensory hyperexcitability, paraesthesia and pain. There were no differences in sensory or motor excitability parameters when comparing different ATTRv variants.
These progressive changes seen across the disease spectrum in ATTRv-PN suggest that axonal excitability has utility to identify early and progressive nerve dysfunction in ATTRv, regardless of genotype.
Axonal excitability is a promising early biomarker of nerve dysfunction in ATTRv-PN.
The test–retest reliability of large and small fiber nerve excitability testing with threshold tracking
2023, Clinical Neurophysiology PracticeStandard nerve excitability testing (NET) predominantly assesses Aα- and Aβ-fiber function, but a method examining small afferents would be of great interest in pain studies. Here, we examined the properties of a novel perception threshold tracking (PTT) method that preferentially activates Aδ-fibers using weak currents delivered by a novel multipin electrode and compared its reliability with NET.
Eighteen healthy subjects (mean age:34.06 ± 2.0) were examined three times with motor and sensory NET and PTT in morning and afternoon sessions on the same day (intra-day reliability) and after a week (inter-day reliability). NET was performed on the median nerve, while PTT stimuli were delivered through a multipin electrode located on the forearm. During PTT, subjects indicated stimulus perception via a button press and the intensity of the current was automatically increased or decreased accordingly by Qtrac software. This allowed changes in the perception threshold to be tracked during strength-duration time constant (SDTC) and threshold electrotonus protocols.
The coefficient of variation (CoV) and interclass coefficient of variation (ICC) showed good–excellent reliability for most NET parameters. PTT showed poor reliability for both SDTC and threshold electrotonus parameters. There was a significant correlation between large (sensory NET) and small (PTT) fiber SDTC when all sessions were pooled (r = 0.29, p = 0.03).
Threshold tracking technique can be applied directly to small fibers via a psychophysical readout, but with the current technique, the reliability is poor.
Further studies are needed to examine whether Aβ-fiber SDTC may be a surrogate biomarker for peripheral nociceptive signalling.
In vivo neurophysiological assessment of in silico predictions of neurotoxicity: Citronellal, 3,4-dichloro-1-butene, and benzyl bromoacetate
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Differences in nerve excitability properties across upper limb sensory and motor axons
2022, Clinical NeurophysiologyThe excitability of motor and sensory axons of the main upper limb nerves were compared to characterise the differences between nerves and provide a guide for future studies in human diseases with median neuropathy at the wrist.
Axonal excitability studies were undertaken on median and ulnar motor (APB and ADM) and sensory axons (D2 and D5) and the superficial radial axons (D1) using a threshold tracking technique.
Compared to the median, ulnar motor axons had reduced early depolarising threshold electrotonus (TEd40(10–20 ms) p = 0.02) and superexcitability (p = 0.03). The ulnar sensory axons required a stronger stimulus (p = 0.02) and had a larger rheobase (p = 0.02) than median axons, but were otherwise comparable. The superficial radial axons were “fanned-in” compared to median, and to a lesser degree ulnar axons, with greater resting I/V slope. Mathematical modelling of the radial and median sensory axons suggested that a 15.1% reduction in conductances between nodal and internodal compartments accounted for 82% of this discrepancy.
The excitability parameters of motor and sensory axons are most comparable between median and ulnar nerves.
The present study demonstrates the feasibility of, and provides normative data for, axonal excitability recordings of the radial and ulnar nerves. We suggest the use of ulnar recordings as an alternative to the median nerve in the setting of compressive neuropathy at the wrist.
Fatigue and activity-dependent conduction block in neuromuscular disorders
2022, Clinical Neurophysiology PracticeFatigue is a major disabling problem in patients with neuromuscular disorders. Both nerve demyelination and increased axonal branching associated with collateral sprouting reduce the safety factor for impulse transmission and could cause activity-dependent hyperpolarization and conduction block during voluntary contraction, and thus fatigue. This study aimed to investigate whether activity-dependent conduction block is associated with fatigue in demyelinating neuropathies and lower motor neuron disorders.
This study included 31 patients (17 with chronic inflammatory demyelinating polyneuropathy [CIDP] and 14 with spinal and bulbar muscular atrophy [SBMA]). Sixteen healthy subjects served as normal controls. Fatigue was assessed using the Fatigue Scale for Motor and Cognitive Functions (FSMC). Compound muscle action potential (CMAP) recording and nerve excitability testing after median nerve stimulation in the wrist were performed before and after maximal voluntary contraction of the abductor pollicis brevis for 1 min.
Patients with CIDP/SBMA had prominent fatigue with higher FSMC motor scores (P < 0.0001) than normal controls. After voluntary contractions, CMAP amplitudes decreased significantly in four of the 17 patients with CIDP and one of the 14 patients with SBMA. The reduction in CMAP amplitude was associated with the fatigue score in the motor but not in the cognitive domain. After voluntary contraction, excitability testing showed axonal hyperpolarization in the normal and CIDP/SBMA groups.
In CIDP or SBMA, fatigue is caused by voluntary contraction-induced membrane hyperpolarization and conduction block, presumably due to the critically lowered safety factor due to demyelination or increased axonal branching.
Peripheral fatigue can be objectively assessed using CMAP amplitudes and nerve excitability testing.
Nerve Excitability and Neuropathic Pain is Reduced by BET Protein Inhibition After Spared Nerve Injury
2021, Journal of PainNeuropathic pain is a common disability produced by enhanced neuronal excitability after nervous system injury. The pathophysiological changes that underlie the generation and maintenance of neuropathic pain require modifications of transcriptional programs. In particular, there is an induction of pro-inflammatory neuromodulators levels, and changes in the expression of ion channels and other factors intervening in the determination of the membrane potential in neuronal cells. We have previously found that inhibition of the BET proteins epigenetic readers reduced neuroinflammation after spinal cord injury. Within the present study we aimed to determine if BET protein inhibition may also affect neuroinflammation after a peripheral nerve injury, and if this would beneficially alter neuronal excitability and neuropathic pain. For this purpose, C57BL/6 female mice underwent spared nerve injury (SNI), and were treated with the BET inhibitor JQ1, or vehicle. Electrophysiological and algesimetry tests were performed on these mice. We also determined the effects of JQ1 treatment after injury on neuroinflammation, and the expression of neuronal components important for the maintenance of axon membrane potential. We found that treatment with JQ1 affected neuronal excitability and mechanical hyperalgesia after SNI in mice. BET protein inhibition regulated cytokine expression and reduced microglial reactivity after injury. In addition, JQ1 treatment altered the expression of SCN3A, SCN9A, KCNA1, KCNQ2, KCNQ3, HCN1 and HCN2 ion channels, as well as the expression of the Na+/K+ ATPase pump subunits. In conclusion, both, alteration of inflammation, and neuronal transcription, could be the responsible epigenetic mechanisms for the reduction of excitability and hyperalgesia observed after BET inhibition. Inhibition of BET proteins is a promising therapy for reducing neuropathic pain after neural injury.
Neuropathic pain is a common disability produced by enhanced neuronal excitability after nervous system injury. The underlying pathophysiological changes require modifications of transcriptional programs. This study notes that inhibition of BET proteins is a promising therapy for reducing neuropathic pain after neural injury.